Herpes simplex virus type I (HSV-1) infection is often asymptomatic or may produce recurrent lesions in and around the mouth, commonly called cold sores. HSV can also infect the tissues of the eye. Ocular herpetic disease, typically caused by HSV-1 either through primary infection or reactivation from the trigeminal ganglia (TG), can have serious sequelae, including permanent corneal scarring and blindness. Herpes stromal keratitis (HSK) is the most common cause of infectious blindness in the developed world, and worldwide produces over 40,000 new cases of severe vision impairment or blindness each year. Interestingly, the majority of HSK tissue damage is thought to be immune-mediated rather than resulting from direct lytic effects of the virus. Even after the virus has successfully been cleared, high levels of inflammatory cytokines and chemokines, immune cell infiltrates, and lymphangiogenesis persist. How HSV-1 infection of the eye leads to this chronic inflammatory syndrome is not well understood. By studying cellular factors that influence the host immune response, we will delineate the cascade of events that begin with viral infection and end with chronic inflammation and vision loss. This proposal represents a continuation of our studies of HSK that were originally funded as an R21. We have previously shown that for HSV-1 ocular infection, HVEM expression is important for eye infection and related disease. HVEM is a type I transmembrane protein of the TNF-receptor superfamily. HVEM is expressed on most cell types, including T cells, B cells, monocytes, neutrophils, epithelial cells, and dendritic cells. HVEM plays an important role in activation and inhibition of lymphocytes in a variety of immune responses. Although HVEM was first identified as a viral entry receptor, our preliminary data indicate this protein is not important for entry during ocular HSV-1 infection but rather has other important non-entry effects on the host immune response. The studies proposed here will address the immunomodulatory functions of HVEM during ocular HSV-1 infections, determine the cell type in which HVEM is expressed and is functionally active, and explore the role of the HVEM ligands BTLA, LIGHT, and CD160 in HSV-mediated ocular pathogenesis. By investigating how HVEM and its ligands contribute to HSK, we will better understand the viral-host interactions leading to an inflammatory syndrome that persists in the absence of replicating virus, providing a basis for therapeutic interventions for HSK directed at the aberrant immune response that targets the cornea that leads to HSK.